New EU Regulation Set To Drive Clinical Trial Harmonization
By Ed Miseta, Chief Editor, Clinical Leader
Sponsor companies conducting clinical trials in the European Union (EU) are currently regulated by EU Directive 2001/20/EC, which provides guidance on clinical trial applications and conduct. Unfortunately, Directives always have to be transposed into National law. By transposing, different countries interpret Directives in slightly different ways. Every country has its own national legislation, resulting in different submission requirements, timelines, classifications, and safety reporting. The result of this lack of harmonization is a complicated and expensive trial process.
“Twenty-eight countries in the EU could potentially have 28 different submission requirements,” says Dr. Martine Dehlinger-Kremer, Global VP, Medical and Regulatory Affairs for SynteractHCR. “This has a distinct adverse effect on the ability of sponsors to conduct trials in the EU. The costs of conducting clinical trials in the EU have increased since the implementation of the directive, and the increase for smaller companies is even sharper.”
Dehlinger-Kremer notes insurance fees for sponsors have increased 800 percent for sponsors, while administrative costs for non-commercial sponsors have increased 98 percent. The delay for launching a trial has increased by 90 percent, and there seems to be little cooperation between the member states. The end result? The number of clinical trial applications in the EU fell by 25 percent from 2007 to 2011.
Out With The Old, In With The New
Repealing Directive 2001/20/EC is obviously seen by many as the key to implementing harmonization. Standing by to replace the directive is EU Regulation number 536/3014 of the European Parliament & The Council, which relates to clinical trials on medicinal products for human use. The directive, which is being modified to become a regulation, has been revised to increase interest in conducting trials in the EU, requires no national interpretation, and will create standardization while still leaving room for national laws.
“We clearly needed some changes in order to keep the EU as an attractive destination for clinical trials,” states Dehlinger-Kremer. “The goals of the new regulation are to make the EU more attractive for clinical research, curtail the decreasing number of clinical investigations taking place in humans in the EU, and maintaining the high standards of patient safety that currently exist. As written, the new Regulation is poised to do all three.”
The new regulation was adopted by both the European Parliament and the Council of Ministers in 2014, and was signed off on and published in the Official Journal the same year. It is expected to become effective in mid-2016. One pre-condition for the launch is an operational database for clinical trials and a portal for submissions. Both will be set up by the European Medicines Agency. Six months after they become functional, the Regulation will go into effect.
An Overhaul Of The Existing System
A new process will attempt to harmonize the authorization procedure for regulatory and EC approval. Clinical trial sponsors will be required to submit a single application for authorization of a trial to a reporting EU member state (RMS) through the new portal. The process is the same regardless of whether the trial will take place in one or multiple EU states. When the application is complete, the assessment of the application will then be conducted in two parts.
Part I is an assessment of the scientific, therapeutic, and safety aspects of the study performed by the RMS. A draft assessment report will be prepared and sent to all concerned EU member states for review. An assessment report prepared by the RMS will conclude if the conduct of the clinical trial is acceptable, unacceptable, or acceptable subject to certain conditions. The report will be applicable in all EU member states, although member states may, in limited circumstances (as specified in the regulation), disagree with the conclusion.
Part II of the assessment will allow EU member states to assess the application based on their national and ethical requirements relating to trial conduct. Each state will continue to determine the composition of its Ethics Committee and organize the review process.
“The benefits of such a system are quite dramatic,” notes Dehlinger-Kremer. “There will be a single application submitted, as opposed to a possible 28, one for each member state. There will also be a single decision made through the EU portal. Each step in the process will be conducted within a set number of days, and authorizations will expire after two years if no subject is enrolled in the trial. Trial applications can be withdrawn at any time prior to approval, and can also be re-submitted. Each member state will set its own fees.”
Stakeholders, including EFPIA, Vaccine Europe, EORTC, EUCROF, ARCO, and member states will be consulted on the building of the portal. Initial sessions focused on the discussion and consolidation of requirements foreseen by the Regulation to be applied to the portal. A second set of sessions, started in March 2015, focused on the review of process grouping of consolidated requirements.
Improved Flexibility and Transparency
Other changes in the new Regulation pertain to increasing monitoring flexibility and transparency, and simplifying safety reporting. Monitoring can now be light or heavy, depending on the nature and objective of the trial. Sponsors are able to evaluate the extent and nature of the monitoring, which will help to open the door for risk-based monitoring (RBM).
Trial transparency will be increased via studies being made publicly available in an EU database. Detailed summaries of the studies, including a summary in plain language, must be submitted within one year of termination of the trial. Dehlinger-Kremer notes clinical study reports submitted to support a marketing application must be loaded, regardless of whether or not the application is approved. Penalties will be enforced in the event of failure to adhere to the transparency requirements.
Safety reporting will also be simplified via unexpected and adverse action reporting made electronically, directly into the EudraVigilance data processing network and management system. If a clinical trial uses more than one investigational medicinal product (IMP), the sponsor may, if planned for in the protocol, submit a single safety report for all IMPs used in the trial.
Although the new Regulation will be a significant improvement over Directive 2001/20/EC, some challenges will likely remain for sponsors conducting trials in the EU. Dehlinger-Kremer believes legal representation is one issue that may continue to be a problem. A legal representative is not mandatory if the Member State chooses to require a contact person in the territory who will be the addressee for all communications with the Sponsor. In this regard, the new Regulation lacks a harmonized approach, as each Member State may choose a different approach.“ Every time there change of any type, you will have pessimists complaining about it,” adds Dehlinger-Kremer. “There are certainly aspects of this Regulation that some people won’t like. But if you look at it in comparison to what we have now, it is a huge improvement, and will greatly simplify the entire process of performing trials in the EU. That will be good news for sponsors, CROs, and patients.”